TY - JOUR
T1 - Control of pancreatic β cell regeneration by glucose metabolism
AU - Porat, Shay
AU - Weinberg-Corem, Noa
AU - Tornovsky-Babaey, Sharona
AU - Schyr-Ben-Haroush, Rachel
AU - Hija, Ayat
AU - Stolovich-Rain, Miri
AU - Dadon, Daniela
AU - Granot, Zvi
AU - Ben-Hur, Vered
AU - White, Peter
AU - Girard, Christophe A.
AU - Karni, Rotem
AU - Kaestner, Klaus H.
AU - Ashcroft, Frances M.
AU - Magnuson, Mark A.
AU - Saada, Ann
AU - Grimsby, Joseph
AU - Glaser, Benjamin
AU - Dor, Yuval
N1 - Funding Information: Y.D. was supported by grants from JDRF, NIH (Beta-cell Biology Consortium), ICRF (Barbara Goodman PC-RCDA), EU (ERC and the Seventh Framework Programme under grant agreement n°241883), the Leona M. and Harry B. Helmsley Charitable Trust, and the Dutch Friends of Hebrew University. B.G. was supported by a grant from JDRF. F.M.A. was supported by the Wellcome Trust. This work was supported in part through core services provided by the DERC at the University of Pennsylvania from a grant sponsored by NIH DK 19525. J.G. is an employee and shareholder of Hoffmann-La Roche. We thank Chris Wright for the generous gift of pdx1 antisera; Antonello Pileggi and Camillo Ricordi for advice on islet transplantation; and Dick Insel, Avigail Dreazen, and Oded Meyuhas for discussions.
PY - 2011/4/6
Y1 - 2011/4/6
N2 - Recent studies revealed a surprising regenerative capacity of insulin-producing β cells in mice, suggesting that regenerative therapy for human diabetes could in principle be achieved. Physiologic β cell regeneration under stressed conditions relies on accelerated proliferation of surviving β cells, but the factors that trigger and control this response remain unclear. Using islet transplantation experiments, we show that β cell mass is controlled systemically rather than by local factors such as tissue damage. Chronic changes in β cell glucose metabolism, rather than blood glucose levels per se, are the main positive regulator of basal and compensatory β cell proliferation in vivo. Intracellularly, genetic and pharmacologic manipulations reveal that glucose induces β cell replication via metabolism by glucokinase, the first step of glycolysis, followed by closure of K ATP channels and membrane depolarization. Our data provide a molecular mechanism for homeostatic control of β cell mass by metabolic demand.
AB - Recent studies revealed a surprising regenerative capacity of insulin-producing β cells in mice, suggesting that regenerative therapy for human diabetes could in principle be achieved. Physiologic β cell regeneration under stressed conditions relies on accelerated proliferation of surviving β cells, but the factors that trigger and control this response remain unclear. Using islet transplantation experiments, we show that β cell mass is controlled systemically rather than by local factors such as tissue damage. Chronic changes in β cell glucose metabolism, rather than blood glucose levels per se, are the main positive regulator of basal and compensatory β cell proliferation in vivo. Intracellularly, genetic and pharmacologic manipulations reveal that glucose induces β cell replication via metabolism by glucokinase, the first step of glycolysis, followed by closure of K ATP channels and membrane depolarization. Our data provide a molecular mechanism for homeostatic control of β cell mass by metabolic demand.
UR - http://www.scopus.com/inward/record.url?scp=79953734660&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2011.02.012
DO - 10.1016/j.cmet.2011.02.012
M3 - مقالة
C2 - 21459328
SN - 1550-4131
VL - 13
SP - 440
EP - 449
JO - Cell Metabolism
JF - Cell Metabolism
IS - 4
ER -
